The quality of life for millions of Americans is adversely affected by salivary gland dysfunction. It is estimated that up to 20% of adults in the US will suffer from xerostomia. The morbidity of this chronic condition is very high, leading in extreme cases to malnourishment. The decreased ability to produce adequate levels of saliva has been associated with numerous subjective and objective functional deficits including the sensation of oral dryness (xerostomia);difficulty with speaking, mastication and swallowing;and an increased susceptibility to caries development and opportunistic infections (e.g., Candida albicans). Treatments are often only partially effective, frequently producing adverse side-effects and usually requiring life-long use. An important first step in improving these treatments is a thorough understanding of the molecular pathways involved in secretion. While substantial advances have been made in our understanding of exocrine gland function and regulation, there remain significant gaps in our knowledge. In particular, we have not yet achieved a clear picture of the synergisms required among signaling pathways and effector molecules to modulate fluid production from salivary glands. We shall address this problem using a multi-scale mathematical and computational model. Unlike purely experimental work, such mathematical models are able to provide an overall understanding of how the behavior of a complex system depends on the behaviors of its constituent elements. Initially we shall develop models of individual parotid acinar and duct cells, and couple these models into a large-scale model of a prototypical secretory unit of a single acinus and associated duct. The model will then be validated and tested against a large set of existing experimental results, and will be used to develop further experiments to test hypotheses about salivary gland function and regulation. In particular, we will examine how intercellular coupling affects salivary secretion, how secretion depends on the spatial positioning and functioning of the various ion channels, and how oscillations in the intracellular calcium concentration affect saliva secretion. Project Narrative: Salivary gland dysfunction is a problem for millions of people, with a significant impact on their quality of life. Although some treatments exist, development of improved therapies is hampered by our limited understanding of exactly how saliva secretion is controlled. We shall combine experimental investigations with a computational model to study the mechanisms of saliva secretion and control, and use this model to guide additional experiments.